The proposed 5-year study examines the effects of a cognitive behavioral stress management (CBSM) intervention (including relaxation training and cognitive restructuring) on physical health status and illness burden in 150 (after attrition) patients diagnosed with Chronic Fatigue Syndrome (CFS). The study tests the efficacy of a conceptual model which holds that the interaction of psychological factors (distress and depression associated with either CFS related symptoms or other stressful life events) and immunologic dysfunction (elevations in cytokines such as tumor necrosis factor [TNF]-alpha and the macrophage activation marker, neopterin) contribute to: (a) the exacerbation of physical symptoms associated with CFS (e.g., fatigue, joint pain, fever) and subsequent increases in illness burden (operationalized as disruptions in daily activities due to fatigue and related physical symptoms); and (b) further dysfunction in the immune system (e.g., impaired lymphocyte proliferative responses to phytohemagglutinin [PHA] and natural killer cell cytotoxicity [NKCC]). The proposed revised study tests this model experimentally by first evaluating the effects of a 10 week group CBSM intervention upon the primary health outcome variables: physical health status (CFS symptoms), fatigue severity, CFS-related illness burden and functional quality of life. Secondly, this study examines the role of two sets of hypothesized mediator variables: (l) reductions in psychological distress and depression levels; and (2) immune system modulation (less impaired NKCC and PHA responsivity, lowered TNF-alpha peptides and TNF-type II receptors in serum, reduced neopterin levels, reduced numbers of lymphocyte subsets expressing activation markers). To bring about these effects the intervention is hypothesized to directly modulate a set of psychosocial intervention targets that we hypothesize will influence the mediator variables. These intervention targets include reductions in distorted cognitive appraisals, greater use of active and engaging coping strategies, increased coping self-efficacy and increased perceptions of social support provisions. This is a randomized experiment with a 12-week CBSM (plus education and standard care) condition vs. an Education plus standard care (ED/SC) control condition, At the end of the 12-week CBSM intervention, the experimental group will continue on a standard of care regimen and will be monitored for their adherence to the techniques learned in the CBSM intervention and for intercurrent medical treatment. At the end of the 12-week ED/SC period the control group will be subsequently monitored as they continue on their standard of care. We will follow subjects at 6 and 12 months post-CBSM to assess treatment carryover and to correlate prospectively pre-post CBSM changes in mediator and health outcome variables measured at these follow-up points.